Xanax poisoning is more dangerous when combined with other CNS depressants like alcohol. Nevertheless, fatal cases of pure alprazolam overdose have been reported 1. Death following hospital admission is rare. The combination of alprazolam with opioids seems to have the highest mortality2. Based on studies in rodents, a lethal dose of alprazolam could theoretically be as low as 25 mg in humans.
During recent decades benzodiazepines like Xanax have become the most commonly used drugs in self-poisoning3.
Xanax Poisoning Cheatsheet
- Xanax overdose is common due to its wide availability.
- Xanax overdose is not as benign as previously thought and can be lethal.
- Xanax is relatively more toxic in overdose than other benzodiazepines, possibily due to its enhanced absorption and shorter half-life.
- Xanax overdose is more dangerous when combined with other depressants like alcohol, barbituates, anticonvulsants or opoioids.
- The lowest estimate of a lethal dose in humans is 25 mg based on animal studies, but in practice this dose is highly unlikely to be fatal.
Benzodiazepines are sedative-hypnotic drugs which have been used clinically since the 1960s.
The Austrian scientist Leo Sternbach, discovered the first benzodiazepine in 1954, chlordiazepoxide. 3 years later, it was marketed as a curative drug under the brand name Librium. Following chlordiazepoxide in 1963, diazepam was released followed by multiple other benzodiazepines over subsequent years.
Xanax is used for:
- the treatment of withdrawal states
- drug-associated agitation
They can be combined with other medicines for procedural sedation. Due to their many uses, benzodiazepines are widely prescribed and almost 50 different agents can be found worldwide. The high prevalence of benzodiazepine overdose reflects availability and their widespread use.
How Xanax Works
Xanax (alprazolam) modulates the gamma-aminobutyric acid A (GABA-A) receptor. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter of the central nervous system – which means that it inhibits brain activity.
The GABA-A receptor is composed of five subunits (alpha, beta, and gamma) ordered in various combinations. The composition of subunits establishes the affinity.
Benzodiazepines bind at the interface of the gamma and alpha subunits and, once bound, lock the GABA-A receptor into a conformation that increases its affinity for GABA. By augmenting receptor binding benzodiazepines usually do not alter the synthesis, release, or metabolism of GABA but rather potentiate its inhibitory actions.
Xanax binding to the GABA-A receptor:
- Increases the flow of chloride ions through the GABA ion channel
- Postsynaptic hyperpolarization – making it more difficult for signals to propagate in the brain
- Rarely causes respiratory depression due to the low density of binding sites in the brainstem respiratory center
Symptoms of Xanax Overdose
Common symptoms of overdose include:
- central nervous system (CNS) depression
- decreased rate of breathing
- decreased heart rate
- loss of consciousness possibly leading to coma or death
- impaired balance
- ataxia – the loss of full control of bodily movements
- slurred speech
Severe symptoms of Xanax (alprazolam) overdose include respiratory depression and coma. Respiratory depression just means that your breathing frequency is slow and you breath in less air (lower tidal volume). Rarely, impaired breathing can result in irreversible hypoxic brain damage (< 1% of cases).
How Dangerous Is Xanax Poisoning?
Doctors have historically considered pure benzodiazepine overdose to be relatively harmless in comparison with several other drugs like tricyclic antidepressants 4. For example, one paper published in 1988 begins with this sentence 5:
Intentional benzodiazepine (BZD) overdose is usually a benign condition frequently encountered in the emergency department of hospital.
Yet pure alprazolam (Xanax) overdose is far from harmless in some cases. One study on 702 patients hospitalized due to benzodiazepine poisoning6 found complications in 9.8% of cases:
- 46 cases of aspiration pneumonia
- 16 cases of pressure injury to skin and muscles with or without transient nerve paralysis or renal affection
- 4 cases of hypotension and irreversible cardiac arrest
- 1 case each of the following: irreversible hypoxic brain damage, hypotension, transient cardiac arrest, hemorrhagic pancreatitis, transient severe liver insufficiency, pneumothorax, urinary tract infection, paralysis of the vocal cords, seizures, laryngeal bleeding.
Individuals with chronic pulmonary disease and the elderly were more likely to suffer these complications.
Xanax vs Other Benzodiazepines in Overdose
Alprazolam (Xanax) is relatively more toxic in overdose than other benzodiazepines. Consider this conclusion in Isbister’s 2004 paper 7:
Alprazolam was significantly more toxic than other benzodiazepines. The increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review.
Next consider these data7:
|Outcome||Alprazolam (n = 131)||Diazepam (n = 823)||Other benzodiazepine (n = 1109)|
|LOS (median)||19.4 h||15.6 h||16.3 h|
LOS = length of hospital stay.
Note that alprazolam (Xanax):
- was associated with a higher rate of ICU admissions
- more frequently required the treatment flumazenil (a drug that blocks the effect of benzodiazepines)
- more frequently required ventilation
- was more likely to result in coma
- was associated with a longer length of stay (LOS) in the hospital
This study provides evidence that alprazolam may be intrinsically more toxic than other benzodiazepines.
Many factors may account for the greater toxicity of alprazolam poisoning. Alprazolam not only increased LOS and ICU admission speed, but increased the use of interventions to prevent complications of respiratory depression: mechanical ventilation and flumazenil administration.
Physicians have raised concerns that alprazolam is over-prescribed for panic disorder. Isbinster et. al. found that 85% of alprazolam prescriptions were for panic disorder, stress, depression or mixed anxiety or depression.
Suicidal ideation and suicide attempts are more prevalent in individuals with panic disorder than in the general population. While those receiving alprazolam are at increased risk of suicidal behaviour (by virtue of the psychiatric diagnoses), alprazolam itself really diminishes suicidal ideation.
Both strength and variety of pills/capsules determines quantity per prescription. Initially accessible 0.25 mg, 0.5 mg and 1 mg strengths, the 2 mg tablet of alprazolam was introduced for panic disorder in which larger doses are used. So an individual taking alprazolam has access to relatively large quantities of drugs that is easily ingestible.
Xanax Overdose Summary
Here are some quick facts about Xanax overdose:
- Cases of benzodiazepine overdose in general increased from their introduction in the 60s to peak in the 90s. The popularity and availability of benzodiazepines has led to their frequent use in self-poisoning.
- Cases of self-poisoning with Xanax rose from the late 80s, peaked in the 90s and has remained constant ever since.
- Ingestion of alprazolam alone is rarely lethal. Most reported fatalities associated with Xanax result from the co-ingestion of CNS depressants (e.g., combining alcohol and alprazolam or opioids and alprazolam).
- Based on theoretical predictions, a lethal dose of Xanax could be as low as 25 mg in some individuals. (For comparison, 0.25 – 0.5 mg is the typical starting dose for alprazolam). In practice, it’s difficult to overdose on Xanax alone.
- Relative to other benzodiazepines, Xanax is more toxic in overdose ( Alprazolam is relatively more toxic than other benzodiazepines in overdose. The median length of stay in a hospital after Xanax overdose is longer than for other benzodiazepines.
- Flumazenil is used to treat Xanax overdose in conjunction with other measures. Flumazenil is a GABA antagonist – it opposes the effects of benzodiazepines at the receptor level.
- One study6 reported that of 702 cases of benzodiazepine overdose:
- 144 ingested benzodiazepines alone
- 200 poisoned themselves with benzodiazepine and alcohol
- 358 congested benzodiazepine and a miscellaneous drug
- Complications in 10% of cases were reported and 5 cases were fatal. So of 702 hospital admissions associated with benzodiazepine poisoning, less than 1% were fatal.
Calculating The LD50 of Xanax (Alprazolam)
Unsurprisngly, there’s no published LD50 of alprazolam in humans. To do that experiment, you’d need to actually kill people. However, the LD50 of Xanax has been studied in rats and was reported to be in the range of 331-2171 mg/kg. This dose corresponds to 25 – 163 mg in humans. Why is estimated LD50 of alprazolam lower in humams than rodents? Because we need to adjust for the surface area of the organism, which entails dividing the LD50 in rodents by 13.2 to convert it the adjusted human dose.
This means that Xanax doses as low as 25 mg could be lethal in some people. However this prediction is theoretical and not really born out in the biomedical literature. In reality lethal overdose due to alprazolam alone is quite rare, though as we’ve discussed there can be serious complications (e.g., irreversible hypoxic brain damage).
Originally published in Alprazolam is relatively more toxic than other benzodiazepines in overdose (2004):
Only a few overdoses due to alprazolam alone have been reported until now with postmortem blood concentrations ranging from 0.12 to 0.39 mg/l. McCormick et al. presented two patients who attempted suicide with alprazolam by ingestion of 20–30 1-mg tablets and 60 1-mg tablets, respectively. These patients had markedly elevated serum concentrations, ten times greater than therapeutic doses, in the ranges of 0.25–0.55 mg/l and 0.20– 0.30 mg/l, without significant alterations in vital signs or CNS depression.
The highest postmortem blood concentration of alprazolam described in the literature was 2.1 mg/l. In our case, a-hydroxyalprazolam was not detected in the blood. The concentration of alprazolam in liver was 9.2 mg/kg (a-hydroxyalprazolam concentration was 0.83 mg/kg), in bile it was 2.8 mg/l (1.3 mg/l of a-hydroxyalprazolam) and in the stomach contents only alprazolam was detected with a concentration of 13 mg in 110 ml.
- Dart, Richard C. (1 December 2003). Medical Toxicology (3rd ed.). USA: Lippincott Williams & Wilkins. p. 811. ISBN 978-0-7817-2845-4 ↩
- Michaud K, Augsburger M, Romain N, Giroud C, Mangin P. Fatal overdose of tramadol and alprazolam. Forensic Sci Int. 1999;105(3):185-9. ↩
- Willox DGA. Self poisoning. A review of patients seen in the Victoria Infirmary. Glasgow. Scott Med ] 1985: 30: 220-4. ↩
- Divoll M, Greenblatt DJ, Lacasse Y, Shader RI. Benzodiazepine overdosage: plasma concentrations and clinical outcome. Psychopharmacology (Berl). 1981;73(4):381-3. Psychopharmacology 1981: 73: 381-3. ↩
- Lheureux P, Askenasi R. Specific treatment of benzodiazepine overdose. Hum Toxicol. 1988;7(2):165-70. ↩
- Höjer J, Baehrendtz S, Gustafsson L. Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med. 1989;226(2):117-22. ↩ ↩2
- Isbister GK, O’regan L, Sibbritt D, Whyte IM. Alprazolam is relatively more toxic than other benzodiazepines in overdose. Br J Clin Pharmacol. 2004;58(1):88-95. ↩ ↩2